Docetaxel in the management of PSA progression following primary androgen deprivation for prostate cancer [Elektronische Ressource] / vorgelegt von Igor Cordia
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Docetaxel in the management of PSA progression following primary androgen deprivation for prostate cancer [Elektronische Ressource] / vorgelegt von Igor Cordia

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44 pages
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Aus dem Zentrum für Operative Medizin der Universität zu Köln Klinik und Poliklinik für Urologie Direktor: Universitätsprofessor Dr. med. Udo Engelmann Docetaxel in the management of PSA progression following primary androgen deprivation for prostate cancer Inaugural#Dissertation zur Erlangung der Doktorwürde der Hohen Medizinischen Fakultät der Universität zu Köln vorgelegt von Igor Cordia aus Leeuwarden, Niederlande Promoviert am: 15 Juli 2009 Gedruckt mit Genehmigung der Medizinischen Fakultät der Universität zu Köln 2009 Druckerei The Print, Leiden 2 Dekan: Universitätsprofessor Dr.med. J. Klosterkötter 1. Berichterstatter: Universitätsprofessor Dr.med. A. Heidenreich 2. Berichterstatter: Universitätsprofessor Dr.med. U. Engelmann Ich erkläre hiermit, dass ich die vorliegende Dissertationsschrift ohne unzulässige Hilfe Dritter und ohne Benutzung anderer als der angegebenen Hilfsmittel angefertigt habe; die aus fremden Quellen direkt oder indirekt übernommenen Gedanken sind als solche kenntlich gemacht. Bei der Auswahl und Auswertung des Materials sowie bei der Herstellung des Manuskriptes habe ich Unterstützungsleistungen von den in der Danksagung erwähnten Personen erhalten. Weitere Personen waren an der geistigen Herstellung der vorliegenden Arbeit nicht beteiligt.

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Publié le 01 janvier 2009
Nombre de lectures 49
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Aus dem Zentrum für Operative Medizin der Universität zu Köln Klinik und Poliklinik für Urologie Direktor: Universitätsprofessor Dr. med. Udo Engelmann  
                    Inaugural#Dissertation zur Erlangung der Doktorwürde der Hohen Medizinischen Fakultät der Universität zu Köln   vorgelegt von Igor Cordia aus Leeuwarden, Niederlande     Promoviert am: 15 Juli 2009  
                                              Gedruckt mit Genehmigung der Medizinischen Fakultät der Universität zu Köln 2009 Druckerei The Print, Leiden  
 
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 Dekan: Universitätsprofessor Dr.med. J. Klosterkötter 1. Berichterstatter: Universitätsprofessor Dr.med. A. Heidenreich 2. Berichterstatter: Universitätsprofessor Dr.med. U. Engelmann      Ich erkläre hiermit, dass ich die vorliegende Dissertationsschrift ohne unzulässige Hilfe Dritter und ohne Benutzung anderer als der angegebenen Hilfsmittel angefertigt habe; die aus fremden Quellen direkt oder indirekt übernommenen Gedanken sind als solche kenntlich gemacht.  Bei der Auswahl und Auswertung des Materials sowie bei der Herstellung des Manuskriptes habe ich Unterstützungsleistungen von den in der Danksagung erwähnten Personen erhalten.   Weitere Personen waren an der geistigen Herstellung der vorliegenden Arbeit nicht beteiligt. Insbesondere habe ich nicht die Hilfe einer Promotionsberaterin/eines Promotionsberaters in Anspruch genommen. Dritte haben von mir weder unmittelbar noch mittelbar geldwerte Leistungen für Arbeiten erhalten, die im Zusammenhang mit dem Inhalt der vorgelegten Dissertationsschrift stehen. Die Dissertationsschrift wurde von mir bisher weder im Inland noch im Ausland in gleicher oder ähnlicher Form einer anderen Prüfungsbehörde vorgelegt.       Köln, im Januar 2009 Igor Cordia
 
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Die Krankengeschichten wurden von mir selbst ausgewertet. Die Sammlung der Patientendaten und Befunde erfolgten ausschließlich durch mich selbst.  
 
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  Herrn Professor Dr. med. A. Heidenreich danke ich für die Überlassung des Themas, sein persönliches Engagement und seine langjährige Unterstützung.  Für die Hilfestellung bei der statistischen Auswertung bedanke ich mich bei Herrn Dipl. Math. Jörg Reitze von More Data GmbH in Gießen.      
  
 
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     ----------------------------------------------------------------------------------------------------------- 6 ------------------------------------------------------------------------------------------------------------------------ 7   !-------------------------------------------------------------------------------------------------------------- 8 1.1 Local disease---------------------------------------------------------------------------------------------------------- 8 1.2 Local progress--------------------------------------------------------------------------------------------------------- 8 1.3 Hormone therapy----------------------------------------------------------------------------------------------------- 9 1.3.1 Androgen deprivation9--------------------------------------------------------------------------------------------- 1.3.2 Secondary hormonal therapy--------------------------------------------------------------------------------- 10 1.3.3 Chemotherapy----------------------------------------------------------------------------------------------------- 12 1.4 Eficacy---------------------------------------------------------------------------------------------------------------- 19 1.5 Prognostic factors-------------------------------------------------------------------------------------------------- 20 " #$--------------------------------------------------------------------------------------------------------------- 20 % &  &---------------------------------------------------------------------------------------------- 21 3.1 Treatment------------------------------------------------------------------------------------------------------------ 21 3.2 Efycaci---------------------------------------------------------------------------------------------------------------- 22 3.3 Statistical analysis.------------------------------------------------------------------------------------------------- 22 ' (-------------------------------------------------------------------------------------------------------------------- 23 4.1 Patient characteristics--------------------------------------------------------------------------------------------- 23 4.2 Clinical efcaciy------------------------------------------------------------------------------------------------------ 24 4.3 Prognostic factors-------------------------------------------------------------------------------------------------- 25 4.4 Adverse efcest------------------------------------------------------------------------------------------------------ 27 ) --------------------------------------------------------------------------------------------------------------- 29 5.1 Clinical efyacic------------------------------------------------------------------------------------------------------ 29 5.2 Prognostic factors-------------------------------------------------------------------------------------------------- 29 5.3 Treatment associated side efcest------------------------------------------------------------------------------ 31 * ---------------------------------------------------------------------------------------------------------------- 33 + ,--------------------------------------------------------------------------------------------------- 34 - (-------------------------------------------------------------------------------------------------------------- 36 9..--------------------------------------------------------------------------------------------------------------- 44   
 
 
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  AAW ACTH ADT ALT ANT AST AIPC AP CAB EAU ECG EMP EBRT GnRH agonist HRPCA HSR LDH LH LVEF PCA PS PSA PSADT RP SWOG ULN  
 
                          
                          
                          
 Antiandrogen withdrawal  Adrenocorticotropic Hormone  Antiandrogen hormone therapy  Alanine aminotransferase  Absolute neutrophil count  Aspartate aminotransferase  Androgen#independent prostate cancer  Alkaline phosphatase  Complete antiandrogen blockade  European Association of urology  Electrocardiogram  Estramustine phosphate  External beam radiation therapy  Gonadotropin#releasing hormone Hormone refractory prostate cancer  Hypersensitivity reaction  Lactate dehydrogenase  Luteinising hormone  Left ventricle ejection fraction  Prostate cancer  Performance state  Prostate specific antigen Prostate specific antigen doubling time  Radical prostatectomy  Southwest Oncology Group  Upper normal limit
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 ! 
Prostate cancer (PCA) is the most common lethal malignancy diagnosed in men and the second leading cause of male cancer mortality. An estimated 2.6 million new cases of PCA are diagnosed each year. Over 60 years ago, Huggins and Hodges discovered androgen deprivation as a first#line therapy for metastatic PCA, leading to remissions lasting 2 to 3 years(49). In most men PCA progresses to an androgen#independent state, resulting in wide spread metastasis and eventually death. Multiple hormone manipulations as different forms of chemotherapy have been developed. Until recently, all these second line therapies were mere palliative. Since the publication of the Southwest Oncology Group (SWOG) 99#16 and TAX 327 studies, which demonstrated a survival benefit for docetaxel#based therapy, there has been a change in prospective in the treatment of hormone refractory prostate cancer (HRPCA)(80, 108). These two studies have set a new standard of care for this disease. From this point of view, we decided to compare three second#line docetaxel#based therapies, docetaxel monotherapy given weekly, docetaxel monotherapy given every three weeks and docetaxel combined with mitoxantrone in its clinical efficacy and treatment associated toxicity in a retrospective, case#control study. First, an overview of treatment options for prostate cancer in advancing grade will be presented.
 .  In a localised state of disease, several treatment options are available as a curative therapy for prostate cancer. Depending on tumour stage, Gleason score, and life expectancy of the patient, the physician should decide the optimal treatment. According to guidelines of the European Association of Urology (EAU) the standard treatment for well,#and moderately differentiated tumours and < 10#year life expectancy is watchful waiting(3). In patients with a longer life expectancy, the radical prostatectomy (RP) is the treatment of choice. Fifteen# year progression#free survival rates without evidence of metastatic disease have been reported to be 80 to 85 percent, for selected men with organ#confined disease(82, 118). An alternative to the radical prostatectomy forms the radiotherapy, for poorly differentiated tumours recommended in combination with hormonal therapy for 2#3 years.
" .  About 10 to 20 percent of men with prostate cancer present with metastatic disease, and in many others, metastases develop despite treatment with surgery or radiotherapy. Currently, salvage prostatectomy is the only curative treatment option for selected patients with local
 
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recurrence after radiation therapy(14, 104). Salvage radiation after local progression following RP, achieves a durable response in a fourth of the patients 10 years after the initiation of salvage radiation therapy(76). 30#70% of the patients experience a decrease in their PSA to an undetectable range(10).
% /  %   In patients with advanced disease, i.e. suspicion of systemic disease, the initial therapy is medical or surgical androgen deprivation (ADT). It consists of a strategy in which the androgen receptor of target cells is not activated via either reduction in testosterone production or androgen receptor blockade and combinations thereof. In metastatic disease, a rapid response to ADT is seen. In about 80% percent of men, primary ADT leads to symptomatic improvement and a reduction in serum levels of prostate#specific antigen (PSA)(19). Serum testosterone levels should be evaluated independent of the type of primary ADT, because in 10% of the patients, the serum testosterone level can be normal. The addition of a non#steroidal antiandrogen can therefore achieve temporary therapeutical effects in some patients. In case of complete androgen blockade (CAB), the withdrawal of antiandrogen therapy (AAW) results in a response rate of about 30% with a median response duration of 6 months(75). Interest has arisen to different hormonal strategies which remain normal testosterone serum levels systemically. Oh et al. showed an overall 5 years survival rate of 65% using a combination of flutamide, a non steroidal antiandrogen combined with finasteride, a 5α# reductase inhibitor in patients with rising PSA levels after local treatment for PCA or with newly discovered metastatic disease(70) . Kirby et al. showed no statistical difference in reduction of PSA serum levels between a combination of flutamide with goserelin (GnRH agonist) or finasteride, in a randomized multicenter phase II clinical trial of patients with untreated M1 cancer of the prostate. The reduction PSA at 24 weeks was for the goserelin and flutamide combination 99.1%, goserelin and finasteride combination 98.75% and finasteride and flutamide combination, 97.6%(52). In a pilot study, Tay et all, claim that finasteride provides additional intracellular androgen blockade when added to bicalutamide at first nadir in patients with advanced PCA, showing a duration of control comparable to castration, with preserved sexual function in some patients(112). Further studies should expose the possible benefits of the combination of an antiandrogen with a 5α#reductase inhibitor.
 
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%"     01     Following ADT, the tumour eventually becomes androgen#independent, but still hormone sensitive, a state called androgen#independent prostate cancer (AIPC), with a median time to progression of 18#36 months after castration(12, 19, 25, 90). The median survival of patients with androgen#independent PCA is 10 to 12 months. Postulated mechanisms for androgen insensitivity include increased sensitivity of the androgen receptor(AR) pathway, over expression of the androgen receptor, or AR independent mechanisms (15, 44, 110, 111). In this androgen independent state, prostate cancer has proven to be still sensitive to further hormonal manipulations.
2  Estramustine phosphate (EMP) has been the standard therapy for patients with PSA progression following ADT for a long period of time. EMP is a derivate of estradiol#17β phosphate that expresses cytotoxic effects. EMP, in its dephosphorylated form, binds to microtubule proteins, structural nuclear proteins and the nuclear matrix. It interacts with the P#glycoprotein efflux pump(102). The estrogenic effects have long been assumed but also disputed(2, 113). EMP as a single agent has demonstrated modest response rates of about 20#30% with a median response duration of only 2 to 4 months(6, 17, 47). Albrecht et all showed a PSA response rate of only 28.9% and a high toxicity in a group of hormone refractory prostate cancer patients treated with EMP(1). Kitamura reviewed the use of EMP in patients with advanced PC and showed a 30#35% objective response rate(53). In combination therapy with taxanes, EMP has demonstrated clinical benefit in terms of objective response in patients with measurable metastatic lesions, delaying time of progression, pain relief and decrease in serum PSA(48, 57, 78) (also seena dtacel xeDo estramustinein the section Chemotherapy). EMP is widely disputed because its substantial overall toxicity, reported in up to 40%(54). Because of the major cardiovascular and gastrointestinal side effects therapy with EMP was nearly abounded. After the discovery of the interaction of EMP with calcium in the gut, low# dose EMP therapy had lived a comeback(37).
 
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2 Estrogens have been used for many years in the management of advanced prostate cancer. They influence the pituitary axis by inhibiting the secretion of luteinising hormone (LH), adrenal and 5#alpha#reductase activity. Estrogens achieve response rates of 43#secretion, 80%(55, 101) but are associated with high cardiovascular complications, especially in high doses(2, 69, 85). Transdermal estradiol seems to reduce the risk of thrombosis and could be a promising therapy, although further research should be performed (68).  
34  Ketoconazole in combination has shown its efficacy in patients with advanced prostate cancer over the last decades. Ketoconazole has been used as antifungal agent, but also has revealed inhibiting effects on both testicular and adrenal testosterone production and might even have direct cytotoxic effects. It is a substituted imidazole that prevents the conversion of cholesterol to pregnenolone. Used as a single agent, it has shown minimal response rates in patients with AIP. In combination with hydrocortisone however, Ketoconazole has shown a significant PSA decrease ≥50% in 30 to 80% of the patients, depending on the dose(17, 31, 34, 40, 98, 99). Wilkinson et al. treated 38 patients with HRPCA with intermediate#dose ketoconazole and hydrocortisone. 55.3% of the patients showed a PSA decrease >50% with a median duration of 6 months. 6 patients (15.8%) discontinued therapy due to intolerable side effects, whereas 31.6% reported toxicity related to ketoconazole(115). In 1997, Small et al showed that 62.5% patients treated with ketoconazole and hydrocortisone as a secondary hormonal manipulation to manage disease progression following initial androgen deprivation had ≥50% PSA decrease, maintained for a minimum of 8 weeks. The median duration of response was 3.5 months(98). Up to 50% stable disease has been reported by Trump et al. in a group of 38 patients treated with high dose ketoconazole, lasting for over 90 days(114). In a Phase II study comparing the efficacy and toxicity of ketoconazole/ hydrocortisone with EMP, we recently showed PSA response rates of 61 and 23% with mean progression free interval of 7,5 and 2,9 months, respectively(17).
5  Glucocorticoids (eg, prednisone, dexamethasone, and hydrocortisone) suppress the adrenal steroid genesis by reducing the pituitary production of ACTH. A second possible mechanism of action is direct inhibition of tumour growth by disruption of intracellular signalling
 
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